Reduced Purkinje cell size is compatible with near normal morphology and function of the cerebellar cortex in a mouse model of spinocerebellar ataxia.

Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurodegenerative disease caused by diverse mutations in the Protein Kinase C gamma (PKCγ) gene which is one of the crucial signaling molecules of Purkinje cells. We have previously created a mouse model of SCA14 by transgenic expression of a mutated PKCγ gene causing SCA14 with a mutation in the catalytic domain. Purkinje cells from the mutated mice have a strong reduction of their dendritic tree in organotypic slice cultures typical for increased PKC activity. There was no overt degeneration of Purkinje cells in vivo and the cerebellum appeared morphologically normal with the exception of lobule 7 where abnormal Purkinje cells were present. Besides from mild motor deficits the mice have no major phenotype. We have now done a more extensive study of cerebellar morphology in these mice and show by rapid Golgi staining that there is a marked reduction of Purkinje cell dendritic tree size throughout the cerebellum. Despite this reduction in dendritic tree size, climbing fiber innervation of Purkinje cells as visualized by immunostaining for the vesicular glutamate transporter 2 (vGlut2) appeared normal in most parts of the cerebellum. The same was true for the expression of the activity and plasticity markers pS6, c-Fos and Arc. These finding suggest that the cerebellar cortex in the transgenic mice is functioning fairly normal and that the reduction of dendritic tree size and the increased PKC activity can be compensated in most Purkinje cells. Around cerebellar lobule 7 there was high transgene expression from the L7 promotor and Purkinje cells showed abnormal morphologies. Climbing fiber innervation as well as the expression of the activity and plasticity markers was strongly disturbed in this area. Our results show that there is substantial potential for functional compensation in the cerebellar cortex. In lobule 7, an area with high transgene expression, compensation failed resulting in Purkinje cell degeneration and dysfunction.